The monocyte/macrophage is the precursor of many or most of the foam cells in early atherosclerotic lesions. The proposed studies are designed to enhance our understanding of mechanisms by which these cells take up lipids and mechanisms by which they mobilize stored triglycerides and cholesterol esters. Recent studies in this laboratory demonstrated a high level of neutral triglyceride lipase in macrophages. We propose to explore the regulation of this enzyme and the relation of its activity to observed rates of triglyceride mobilization from previously fat-loaded cells (incubated with fatty acid-albumin or very low density lipoprotein). Parallel studies will address the role of a recently described neutral cholesterol esterase in controlling the build-up of cholesterol ester stores. The activity of this enzyme can be modulated by cyclic AMP-dependent protein kinase. We propose to test whether the activation or responsiveness to activation of the enzyme varies with exposure to hormones, or agents that modulate macrophage functions, state of activation and differentiation of the macrophage or degree of lipid-loading. Macrophages secrete lipoprotein lipase and this has been shown to facilitate uptake of chylomicrons and very low density lipoproteins. Whether its secretion is regulated by insulin and other factors regulating lipoprotein lipase activity in other tissues remains to be determined. We will measure its secretion again as a function of macrophage activation and differentiation. The possibility that dysfunction of the macrophage in diabetic patients may explain their premature atherosclerosis in the absence of hyperlipidemia will be pursued. Macrophages prepared from diabetic animals will be compared with normal macrophages with respect to lipid and lipoprotein metabolism; macrophages from normal animals will be exposed to hormones and metabolites such as those found in diabetics to determine effects on lipoprotein uptake and lipid mobilization. Finally, we will try to test, using perfused segments of aorta, the extent to which triglyceride-rich lipoproteins are taken up by foam cells in early atherosclerotic lesions and the extent to which macrophage lipoprotein lipase is involved in the process. A better understanding of the mechanisms involved in foam cell formations could uncover new methods for intervention.